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Developmental exposure to the endocrine disruptor tolylfluanid induces sex-specific later-life metabolic dysfunction.

ABSTRACT: Endocrine-disrupting chemicals (EDCs) are implicated in the developmental mis-programming of energy metabolism. This study examined the impact of combined gestational and lactational exposure to the fungicide tolylfluanid (TF) on metabolic physiology in adult offspring. C57BL/6?J dams received standard rodent chow or the same diet containing 67?mg/kg TF. Offspring growth and metabolism were assessed up to 22 weeks of age. TF-exposed offspring exhibited reduced weaning weight. Body weight among female offspring remained low throughout the study, while male offspring matched controls by 17 weeks of age. Female offspring exhibited reduced glucose tolerance, markedly enhanced systemic insulin sensitivity, reduced adiposity, and normal gluconeogenic capacity during adulthood. In contrast, male offspring exhibited impaired glucose tolerance with unchanged insulin sensitivity, no differences in adiposity, and increased gluconeogenic capacity. These data indicate that developmental exposure to TF induces sex-specific metabolic disruptions that recapitulate key aspects of other in utero growth restriction models.

SUBMITTER: Ruiz D

PROVIDER: S-EPMC6766412 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Developmental exposure to the endocrine disruptor tolylfluanid induces sex-specific later-life metabolic dysfunction.

Ruiz Daniel D Regnier Shane M SM Kirkley Andrew G AG Hara Manami M Haro Fidel F Aldirawi Hani H Dybala Michael P MP Sargis Robert M RM

Reproductive toxicology (Elmsford, N.Y.) 20190628

Endocrine-disrupting chemicals (EDCs) are implicated in the developmental mis-programming of energy metabolism. This study examined the impact of combined gestational and lactational exposure to the fungicide tolylfluanid (TF) on metabolic physiology in adult offspring. C57BL/6 J dams received standard rodent chow or the same diet containing 67 mg/kg TF. Offspring growth and metabolism were assessed up to 22 weeks of age. TF-exposed offspring exhibited reduced weaning weight. Body weight among f ...[more]

PMID: 31260803

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Project description:BackgroundOrganotin pollutant tributyltin (TBT) is an environmental endocrine disrupting chemical and is a known obesogen and diabetogen. TBT can be detected in human following consumption of contaminated seafood or water. The decrease in muscle strength and quality has been shown to be associated with type 2 diabetes in older adults. However, the adverse effects of TBT on the muscle mass and function still remain unclear. Here, we investigated the effects and molecule mechanisms of low-dose TBT on skeletal muscle regeneration and atrophy/wasting using the cultured skeletal muscle cell and adult mouse models.MethodsThe mouse myoblasts (C2C12) and differentiated myotubes were used to assess the in vitro effects of low-dose tributyltin (0.01-0.5 μM). The in vivo effects of TBT at the doses of 5 and 25 μg/kg/day (n = 6/group), which were five times lower than the established no observed adverse effect level (NOAEL) and equal to NOAEL, respectively, by oral administration for 4 weeks on muscle wasting and muscle regeneration were evaluated in a mouse model with or without glycerol-induced muscle injury/regeneration.ResultsTBT reduced myogenic differentiation in myoblasts (myotube with 6-10 nuclei: 53.9 and 35.8% control for 0.05 and 0.1 μM, respectively, n = 4, P < 0.05). TBT also decreased myotube diameter, upregulated protein expression levels of muscle-specific ubiquitin ligases (Atrogin-1 and MuRF1), myostatin, phosphorylated AMPKα, and phosphorylated NFκB-p65, and downregulated protein expression levels of phosphorylated AKT and phosphorylated FoxO1 in myotubes (0.2 and 0.5 μM, n = 6, P < 0.05). Exposure of TBT in mice elevated body weight, decreased muscle mass, and induced muscular dysfunction (5 and 25 μg/kg, P > 0.05 and P < 0.05, respectively, n = 6). TBT inhibited soleus muscle regeneration in mice with glycerol-induced muscle injury (5 and 25 μg/kg, P > 0.05 and P < 0.05, respectively, n = 6). TBT upregulated protein expression levels of Atrogin-1, MuRF1, myostatin, and phosphorylated AMPKα and downregulated protein expression level of phosphorylated FoxO1 in the mouse soleus muscles (5 and 25 μg/kg, P > 0.05 and P < 0.05, respectively, n = 6).ConclusionsThis study demonstrates for the first time that low-dose TBT significantly inhibits myogenic differentiation and triggers myotube atrophy in a cell model and significantly decreases muscle regeneration and muscle mass and function in a mouse model. These findings suggest that low-dose TBT exposure may be an environmental risk factor for muscle regeneration inhibition, atrophy/wasting, and disease-related myopathy.

Dataset Information

Developmental exposure to the endocrine disruptor tolylfluanid induces sex-specific later-life metabolic dysfunction.

Publications

Developmental exposure to the endocrine disruptor tolylfluanid induces sex-specific later-life metabolic dysfunction.

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